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Principal Investigator: Ralph S Baric
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2022
Award: $350,149
Funding agency: National Cancer Institute
Abstract
Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including
Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory coronavirus
(MERS-CoV) in 2012. In Dec 2019, a third novel CoV designated SARS-CoV-2 emerged in Wuhan China and
has caused over 13 million cases, >570,000 deaths in >220 countries. In the expanding US epidemic, SARS-
CoV2 has caused >137,000 deaths and significantly more severe infections characterized by pneumonia, severe
acute respiratory distress syndrome (ARDS), coagulopathies, and inflammatory disorders. Incredibly, careful
analyses of zoonotic bat CoV has revealed the presence of numerous group 2b SARS-like, group 2c MERS-like
and remarkably, group 1 strains that replicate efficiently in primary human airway or gut enteroid cultures. To
prepare for future CoV calamities, defined diagnostic assays and serologic investigations are essential for
tracking current and future outbreaks and evaluate type specific and broad serologic immunity associated with
population immunity. The goal of this U54 Center Program is to develop novel type- and group-specific serologic
and neutralization assays (Project 1-Baric, Project 2-, Core B and C) designed to characterize the serological
repertoire and to identify key domain-specific mucosal and systemic neutralizing and non-neutralizing antibodies
after SARS-CoV-2 infection. One key underlying hypothesis is that IgA and IgG repertoires are different across
mucosal and systemic compartments and target unique and overlapping epitope domains in the SARS-CoV2 S
glycoprotein. Another underlying hypothesis is that intervention strategies can altered the memory B cell and
antibody repertoires in mucosal and serologic compartments. Finally the program develops novel mouse models
of human disease designed to mechanistically address fundamental immune innate and adaptive interactions
associated with protective immunity. The Project uses novel technologies, basic and applied strategies to build
a portfolio of reagents that map, track and treat SARS-CoV2 and other SARS-like group 2b CoV of the future.
In Aim 1, we evaluate the kinetics, magnitude, durability of type specific neutralizing antibody responses after
infection. Aim 2 characterizes the breadth of the mucosal and systemic serologic repertoires across
Sarbecoviruses. In Aim 3, we characterize the antibodies in the mucosal and serum serologic repertoires using
a variety of in vitro and in vivo platforms, designed to reveal correlates associated with protective immunity. To
achieve our goals, the project interfaces closely with other projects and cores within the Center.
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crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 assay><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 immunity><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cessation of life><China><Chiroptera><Clinical Immunology><CoV emergence><CoV-2><CoV2><Coagulation Disorder><Coagulopathy><Collaborations><Collection><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Country><Da Nang Lung><Data><Death><Diagnostic Reagent><Disease><Disease Outbreaks><Disorder><Epidemic><Epitopes><Future><Glycoproteins><Goals><Human><IgA><IgG><Immune><Immunes><Immunity><Immunoglobulin A><Immunoglobulin G><Immunology><In Vitro><Infection><Inflammatory><Intervention><Intervention Strategies><Investigation><Kinetics><Lentivirinae><Lentivirus><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mainland China><Maps><Measures><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Middle East><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Mucosa><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Murine><Mus><North Carolina><Outbreaks><Outcome><Pathogenicity><Persons><Play><Pneumonia><Population><Public Health><Reagent><Recombinants><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 assay><SARS-CoV-2 epidemic><SARS-CoV-2 exposure><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sarbecovirus><Serodiagnoses><Serological Diagnosis><Serology><Serum><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Specificity><Stiff lung><Study models><Technology><Texas><Therapeutic antibodies><Time><Translational Research><Translational Science><Treatment Protocols><Treatment Regimen><Treatment Schedule><Vaccination><Viral><Virus><Virus-Lenti><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><aged><antibody based therapies><antibody biosynthesis><antibody treatment><antibody-based therapeutics><antibody-based treatment><bleeding disorder><clinical care><clotting disorder><cohort><convalescent plasma><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 assay><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 exposure><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease 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coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunoglobulin biosynthesis><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><interventional strategy><model of human><mouse model><murine model><nCoV><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><new diagnostics><new technology><next generation diagnostics><novel><novel CoV><novel corona virus><novel coronavirus><novel diagnostics><novel technologies><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 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